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Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response
The integrated stress response manifests with the phosphorylation of eukaryotic initiation factor 2α (eIF2α) on serine residue 51 and plays a major role in the adaptation of cells to endoplasmic reticulum stress in the initiation of autophagy and in the ignition of immune responses. Here, we report...
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Published in: | Cell death & disease 2021-01, Vol.12 (1), p.6-6, Article 6 |
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description | The integrated stress response manifests with the phosphorylation of eukaryotic initiation factor 2α (eIF2α) on serine residue 51 and plays a major role in the adaptation of cells to endoplasmic reticulum stress in the initiation of autophagy and in the ignition of immune responses. Here, we report that lysosomotropic agents, including azithromycin, chloroquine, and hydroxychloroquine, can trigger eIF2α phosphorylation in vitro (in cultured human cells) and, as validated for hydroxychloroquine, in vivo (in mice). Cells bearing a non-phosphorylatable eIF2α mutant (S51A) failed to accumulate autophagic puncta in response to azithromycin, chloroquine, and hydroxychloroquine. Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. Altogether, these results point to the unexpected capacity of azithromycin, chloroquine, and hydroxychloroquine to elicit the integrated stress response. |
doi_str_mv | 10.1038/s41419-020-03324-w |
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Here, we report that lysosomotropic agents, including azithromycin, chloroquine, and hydroxychloroquine, can trigger eIF2α phosphorylation in vitro (in cultured human cells) and, as validated for hydroxychloroquine, in vivo (in mice). Cells bearing a non-phosphorylatable eIF2α mutant (S51A) failed to accumulate autophagic puncta in response to azithromycin, chloroquine, and hydroxychloroquine. Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. Altogether, these results point to the unexpected capacity of azithromycin, chloroquine, and hydroxychloroquine to elicit the integrated stress response.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-020-03324-w</identifier><identifier>PMID: 33414432</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/2 ; 631/80/39/2346 ; 692/699/255/2514 ; 96/35 ; 96/47 ; 96/63 ; Animals ; Anti-Bacterial Agents - pharmacology ; Anti-Bacterial Agents - therapeutic use ; Antibiotics ; Antibodies ; Autophagy ; Azithromycin ; Azithromycin - pharmacology ; Azithromycin - therapeutic use ; Biochemistry ; Biomedical and Life Sciences ; Cancer ; Cell Biology ; Cell Culture ; Chloroquine ; Chloroquine - pharmacology ; Chloroquine - therapeutic use ; Dephosphorylation ; Endoplasmic reticulum ; Humans ; Hydroxychloroquine ; Hydroxychloroquine - pharmacology ; Hydroxychloroquine - therapeutic use ; Immune response ; Immunology ; Initiation factor eIF-2α ; Life Sciences ; Medicin och hälsovetenskap ; Mice ; Nelfinavir ; Phagocytosis ; Phosphorylation ; Serine</subject><ispartof>Cell death & disease, 2021-01, Vol.12 (1), p.6-6, Article 6</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021. 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><collection>Directory of Open Access Journals</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tian, Ai-Ling</au><au>Wu, Qi</au><au>Liu, Peng</au><au>Zhao, Liwei</au><au>Martins, Isabelle</au><au>Kepp, Oliver</au><au>Leduc, Marion</au><au>Kroemer, Guido</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2021-01-06</date><risdate>2021</risdate><volume>12</volume><issue>1</issue><spage>6</spage><epage>6</epage><pages>6-6</pages><artnum>6</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>The integrated stress response manifests with the phosphorylation of eukaryotic initiation factor 2α (eIF2α) on serine residue 51 and plays a major role in the adaptation of cells to endoplasmic reticulum stress in the initiation of autophagy and in the ignition of immune responses. Here, we report that lysosomotropic agents, including azithromycin, chloroquine, and hydroxychloroquine, can trigger eIF2α phosphorylation in vitro (in cultured human cells) and, as validated for hydroxychloroquine, in vivo (in mice). Cells bearing a non-phosphorylatable eIF2α mutant (S51A) failed to accumulate autophagic puncta in response to azithromycin, chloroquine, and hydroxychloroquine. Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. 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subjects | 13/2 631/80/39/2346 692/699/255/2514 96/35 96/47 96/63 Animals Anti-Bacterial Agents - pharmacology Anti-Bacterial Agents - therapeutic use Antibiotics Antibodies Autophagy Azithromycin Azithromycin - pharmacology Azithromycin - therapeutic use Biochemistry Biomedical and Life Sciences Cancer Cell Biology Cell Culture Chloroquine Chloroquine - pharmacology Chloroquine - therapeutic use Dephosphorylation Endoplasmic reticulum Humans Hydroxychloroquine Hydroxychloroquine - pharmacology Hydroxychloroquine - therapeutic use Immune response Immunology Initiation factor eIF-2α Life Sciences Medicin och hälsovetenskap Mice Nelfinavir Phagocytosis Phosphorylation Serine |
title | Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response |
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